PROJECT SUMMARY/ABSTRACT Although rodent tumor models are used to determine the underlying neurobiological mechanisms driving can- cer-associated cognitive impairments, a crucial oversight pervasive in the field is that these models are exclu- sively young adults, whereas the human cancer populations they are designed to model are predominantly middle-aged adults. Given that normal aging independently alters relevant neurobiology and cognitive behav- ior, our long-term goal is to determine how aging affects brain physiology and function in the context of chronic disease and to develop effective interventions to prevent or reverse these effects. The overall objective for this project, as a first step in attaining this goal, is to ascertain the extent to which aging affects tumor-induced im- pairments in cognitive function and to identify the neurobiological signature associated with these adverse be- haviors. Therefore, we propose to test the central hypothesis that aging exacerbates tumor-induced neuroin- flammation and early AD neuropathology underlying cognitive impairments using an aged version of an estab- lished mouse model of breast cancer. Two specific aims are proposed to test the central hypothesis. Aim 1 is to determine the effects of aging on cognitive function in the context of cancer. Based on our preliminary data, our working hypothesis is that advanced age increases tumor-induced hippocampal-dependent learning and memory impairments over that of aging or tumors alone. Aim 2 will identify neural alterations due to aging with peripheral cancer that are relevant to cognitive behavior. We postulate, on the basis of our preliminary data, that neuroinflammatory priming caused by aging amplifies expression of proinflammatory cytokines and factors involved in early AD pathology (e.g., amyloid precursor proteins, amyloid beta, tau) in the brains of tumor- bearing mice. The expected outcome for Aim 1 is the identification of specific types or components of cognitive behavior that are modulated by aging with a mammary tumor. Aim 2 will provide the foundation for the mecha- nistic neural pathways underlying these behavioral changes. This contribution is significant because it is a sub- stantial first step in the advancement of cancer modeling and will result in the identification of novel and more translational mechanisms. This mechanistic understanding will allow for the honing of more specific and effec- tive treatment options to improve cancer patient quality of life, and therefore, longevity. The proposed research is innovative, because it is the first to systematically parse out the independent roles of cancer and aging and their combination in the study of a vulnerable and clinically-essential quality-of-life issue for cancer patients: cognition. In addition, the investigation of tumors as a catalyst for early AD pathology is a new approach to the cognitive problems in cancer patients.